Systems and methods for training a statistical model to predict tissue characteristics for a pathology image

ABSTRACT

In some aspects, the described systems and methods provide for a method for training a statistical model to predict tissue characteristics for a pathology image. The method includes accessing annotated pathology images. Each of the images includes an annotation describing a tissue characteristic category for a portion of the image. A set of training patches and a corresponding set of annotations are defined using an annotated pathology image. Each of the training patches in the set includes values obtained from a respective subset of pixels in the annotated pathology image and is associated with a corresponding patch annotation determined based on an annotation associated with the respective subset of pixels. The statistical model is trained based on the set of training patches and the corresponding set of patch annotations. The trained statistical model is stored on at least one storage device.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application Ser. No. 62/515,772, entitled “DATA-DRIVENDIAGNOSTIC METHODS” and filed on Jun. 6, 2017, U.S. ProvisionalApplication Ser. No. 62/515,779, entitled “COMBINED USE OF IMAGE ANDMOLECULAR DATA FOR PATHOLOGY” and filed on Jun. 6, 2017, and U.S.Provisional Application Ser. No. 62/515,795, entitled “PATHOLOGYANALYSIS SYSTEMS AND METHODS” and filed on Jun. 6, 2017, each of whichis herein incorporated by reference in its entirety.

BACKGROUND

Cancer is one of the leading causes of death in the United States. Eachyear over 1.5 million people are newly diagnosed with cancer in theUnited States alone. Over 500,000 Americans die from cancer annually,and many more suffer from it. The burden of the disease is not limitedto cancer patients but extends to their families and social circles. Theloss of a loved one can be devastating, and even when the cancer patientsurvives, the uncertainty is emotionally trying. Cancer exacts aneconomic toll as well: the estimated direct medical costs for cancertreatment in the United States in 2014 were $87.8 billion, and somesources project that this number could exceed $200 billion by 2020. Inaddition to cancer, other burdensome diseases, such as Alzheimer'sdisease, Parkinson's disease, diabetes, cystic fibrosis, sickle cellanemia, and autoimmune diseases, continue to affect the lives ofmillions of people, either directly or indirectly, every year.

While significant resources have been dedicated to treating suchdiseases, in almost all cases, early and accurate detection is crucialto successful outcomes. Furthermore, because many treatments are painfuland carry their own set of patient risks, accurate diagnoses areessential before beginning treatment. It is for that reason thatpreliminary screens such as mammograms, prostate exams, and pap testsare followed up with tissue biopsies when abnormalities are found.

SUMMARY

In some aspects, systems and methods are described for training and/orusing a statistical model to annotate pathology images with one or moretissue characteristics. For example, the described systems and methodsmay be used to examine images of lymph nodes to determine whether or notthose tissues contain indicia of breast cancer.

In various aspects, the training data for the statistical model mayinclude pathology images, such as tissue images, labeled by pathologiststo identify regions of cancer and regions of normal cells. The tissueimages may be microscopic images of tissue samples (e.g., tissueslices). A set of training patches for each pathology image from thetraining data may be defined and provided as input to the statisticalmodel for training. Each training patch may include one or moreannotations describing one of the tissue characteristic categories. Thestatistical model may be trained on the set of training patches and thecorresponding set of annotations. In some embodiments, the annotationsmay be assigned by a pathologist or other medical professional. In someembodiments, the annotations may be assigned based on the output of thestatistical model.

In some embodiments, examples of training patches for which the modelclassified incorrectly are identified, and the model is retrained onthese difficult training patches to improve the performance of themodel. In some embodiments, the statistical model may be used to assignannotations to one or more portions of a pathology image. Inaccurateannotations assigned by processing the pathology image using thestatistical model may be identified, e.g., by a pathologist, andcorresponding subsets of training data may be provided to thestatistical model for retraining, so that the performance of thestatistical model may be improved.

In some aspects, the described systems and methods optionally providefor training and using a model, such as a classifier, to predictprognostic information, such as patient survival time, using featurevalues extracted from the annotated pathology images. For example, thetrained model may be used to predict how well a given patient willrespond to certain treatments based on the predicted prognosticinformation.

In some embodiments, once a statistical model is trained to predicttissue characteristic categories for a pathology image, the pathologyimage may be fully annotated by processing the image using thestatistical model. The fully annotated pathology image may be analyzedto determine values for one or more features. These feature values andcorresponding patient prognostic information may be provided as inputtraining data to a model (e.g., a random forest, a support vectormachine, regression, a neural network, or another suitable model) to themodel to predict prognostic information, such as patient survival time,from sample data for a patient.

In some embodiments, the training data may include known outcomes ofindividuals from whom the training data, e.g., the tissue images, wasobtained. The known outcomes may be, for example, one or more of tumormetastasis, tumor progression, or patient survival related to a cancer.Examples of cancer that may be related with known outcomes include, butare not limited to, breast cancer, lung cancer, ovarian cancer, uterinecancer, cervical cancer, vaginal cancer, colorectal cancer, prostatecancer, skin cancer, or pancreatic cancer. The known outcomes mayalternatively be related to another genetically-based disease, such asAlzheimer's disease, Parkinson's disease, diabetes, cystic fibrosis,sickle cell anemia, or an autoimmune disease.

In some embodiments, the model is trained on data from patients in atreatment group of a clinical trial. The trained model is then used topredict survival data for another treatment group of the clinical trial.The performance of the model to be able to accurately predict survivaldata for patients in the other treatment group is analyzed to determineits effectiveness in correctly identifying a subset of patients that maybenefit from the experimental treatment studied in the clinical trial.In some embodiments, the trained model is used to predict an expectedbenefit of an experimental treatment for candidate patients in a newclinical trial. The information provided as output from the trainedmodel may be used to select patients for the new clinical trial that arelikely to benefit from the experimental treatment, thus improving thechances that the new clinical trial will be successful.

In some aspects, the described systems and methods provide for a methodfor training a statistical model to predict tissue characteristics for apathology image. The method includes accessing annotated pathologyimages. Each of the images includes an annotation describing a tissuecharacteristic category for a portion of the image. A set of trainingpatches and a corresponding set of annotations are defined using anannotated pathology image. Each of the training patches in the setincludes values obtained from a respective subset of pixels in theannotated pathology image and is associated with a corresponding patchannotation determined based on an annotation associated with therespective subset of pixels. The statistical model is trained based onthe set of training patches and the corresponding set of patchannotations. The trained statistical model is stored on at least onestorage device.

In some embodiments, an unannotated portion of the annotated pathologyimage is processed, using the trained statistical model, to predict anannotation of a tissue characteristic category for the unannotatedportion of the image. The predicted annotation is presented to a uservia a user interface. An indication of whether the predicted annotationis accurate is received via the user interface. If the indicationspecifies that the predicted annotation is accurate, the unannotatedportion of the image is associated with the predicted annotation. Insome embodiments, if the indication specifies that the predictedannotation is not accurate, the predicted annotation is updated based onthe received indication. A set of training patches is redefined from theannotated pathology images. The statistical model is retrained based onthe redefined set of training patches and the respective annotations.The retrained statistical model is stored on the storage device. In someembodiments, the updated annotation has a category determined based onthe received indication. In some embodiments, the category for theupdated annotation is a background category.

In some embodiments, defining the set of training patches from theannotated pathology images comprises including in the set of trainingpatches, at least some training patches from each of the plurality oftissue characteristic categories. In some embodiments, the set oftraining patches includes training patches uniformly distributed acrossall of the plurality of tissue characteristic categories. In someembodiments, a distribution across the tissue characteristic categoriesin the set of training patches differs from a distribution across thetissue characteristic categories of annotations in the annotatedpathology images.

In some embodiments, defining the set of training patches from theannotated pathology images comprises including in the set of trainingpatches a training patch associated an annotation for a backgroundcategory. The training patch is located a radius of pixels from anannotation having a category other than the background category.

In some embodiments, defining the set of training patches from theplurality of annotated pathology images comprises including in the setof training patches at least some training patches having an annotationat a center of the respective training patch.

In some embodiments, a dimension of each of the training patches in theset is larger than a corresponding dimension of input to the statisticalmodel. The additional pixels in each of the training patches in the setare included when randomly resampling the respective training patch fordata augmentation.

In some embodiments, the statistical model includes a convolutionalneural network including a plurality of layers, and there is no paddingapplied to an output of any layer of the plurality of layers.

In some embodiments, the statistical model includes a convolutionalneural network including a plurality of layers, and at least one of theplurality of layers, having input of size N*N, a convolution filter ofsize K, and a stride S, is aligned such that (N−K)/S is an integer.

In some embodiments, the tissue characteristic categories includes oneor more categories selected from a group including cancer epithelium,cancer stroma, normal tissue, necrosis, lymphoid, macrophage,lymphocyte, fibroblast, plasma cell, pulmonary macrophage, melanoma,pigmented macrophage, endothelial cell, mitotic figure, nucleoli,nuclear pleomorphism, nerve, adipocyte, peri-neural invasion, epithelialand epithelial tubule formation, and other suitable tissuecharacteristic categories.

In some embodiments, the annotated pathology images are magnified tocreate a magnified set of pathology images. A second set of trainingpatches is defined from the magnified set of annotated pathology images.A second statistical model is trained based on the second set oftraining patches and respective annotations. The trained secondstatistical model is stored on the storage device. In some embodiments,the output of the second trained statistical model is combined with theoutput of the trained statistical model described above using a logicalAND operation or a logical OR operation.

In some aspects, the described systems and methods provide for a methodfor predicting tissue characteristics for a pathology image. Astatistical model trained on multiple annotated pathology images isused. Each of the training pathology images includes an annotationdescribing tissue characteristics for one or more portions of the image.The method includes accessing a pathology image for predicting tissuecharacteristics. A trained statistical model is retrieved from a storagedevice. The statistical model is trained on a set of training patchesand a corresponding set of patch annotations derived from an annotatedpathology image. Each of the training patches in the set includes valuesobtained from a respective subset of pixels in the annotated pathologyimage and is associated with a corresponding patch annotation determinedbased on an annotation associated with the respective subset of pixels.A set of patches is defined from the pathology image. Each of thepatches in the set includes a subset of pixels from the correspondingpathology image. The set of patches is processed using the trainedstatistical model to predict respective annotations for each patch inthe set. The predicted annotations are stored on the storage device.

In some embodiments, a predicted annotation is presented to a user via auser interface. An indication of whether the predicted annotation isaccurate is received via the user interface. If the indication specifiesthat the predicted annotation is accurate, a portion of the pathologyimage is associated with the predicted annotation. The association ofthe portion of the pathology image with the predicted annotation isstored on the storage device.

In some embodiments, the trained statistical model includes aconvolutional neural network including a plurality of layers, and thereis no padding applied to an output of any layer of the plurality oflayers.

In some embodiments, the trained statistical model includes aconvolutional neural network including a plurality of layers, and atleast one of the plurality of layers, having input of size N*N, aconvolution filter of size K, and a stride S, is aligned such that(N−K)/S is an integer.

In some embodiments, a second trained statistical model is retrievedfrom the storage device. The second trained statistical model is trainedon a set of training patches and a corresponding set of patchannotations derived from a magnified annotated pathology image. Theaccessed pathology image is magnified to create a magnified pathologyimage. A second set of patches is defined from the magnified pathologyimage. The set of patches is processed, using the second trainedstatistical model, to predict respective annotations for each patch inthe set. In some embodiments, the output of the second trainedstatistical model is combined with the output of the trained statisticalmodel described above using a logical AND operation or a logical ORoperation.

In some embodiments, a portion of the pathology image is associated witha predicted annotation. The association of the portion of the pathologyimage with the predicted annotation is stored on the storage device.Values for one or more features are extracted from the annotatedpathology image.

In some embodiments, the one or more features are selected from a groupincluding area of epithelium, area of stroma, area of necrosis, area ofcancer cells, area of macrophages, area of lymphocytes, number ofmitotic figures, average nuclear grade, average distance betweenfibroblasts and lymphocytes, average distance betweenimmunohistochemistry-positive macrophages and cancer cells, standarddeviation of nuclear grade, average distance between blood vessels andtumor cells. In some embodiments, a model is trained based on theextracted values for the one or more features to predict an entity ofinterest. In some embodiments, the entity of interest is selected from agroup including survival time, drug response, patient levelphenotype/molecular characteristics, mutational burden, tumor molecularcharacteristics, transcriptomic features, protein expression features,patient clinical outcomes, and other suitable entities of interest.

In some embodiments, the model is trained on the extracted featurevalues by accessing annotated pathology images, training the model basedon the entity of interest and the extracted values for the features fromeach of the annotated pathology images, and storing the trained model onthe storage device. Each of the annotated pathology images is associatedwith the entity of interest, each of the annotated pathology imagesincludes an annotation for a portion of the image, and values areextracted for the features from each of the annotated pathology images.

In some aspects, the described systems and methods provide for a methodfor training a model to predict survival time for a patient. The methodincludes accessing annotated pathology images associated with a firstgroup of patients in a clinical trial. Each of the annotated pathologyimages is associated with survival data for a respective patient. Eachof the annotated pathology images includes an annotation describing atissue characteristic category for a portion of the image. Values forone or more features are extracted from each of the annotated pathologyimages. A model is trained based on the survival data and the extractedvalues for the features. The trained model is stored on a storagedevice.

In some embodiments, the clinical trial is a randomized controlledtrial, and the first group of patients belong to an experimentaltreatment group of the randomized controlled trial. In some embodiments,values for features extracted from annotated pathology images associatedwith a second group of patients are processed using the trained model.The values are processed to predict survival data for patients in thesecond group of patients. The patients in the second group of patientsbelong to a control treatment group of the randomized controlled trial.

In some embodiments, a first prognostic performance of the trained modelfor the experimental treatment group is determined based on thepredicted survival data for the patients in the first group of patientsand respective survival data. A second prognostic performance of thetrained model for the control treatment group is determined based onpredicted survival data for the patients in the second group of patientsand respective survival data. A specificity of a prognostic power of thetrained model is determined by comparing the first prognosticperformance of the trained model for the experimental treatment groupand the second prognostic performance of the trained model for thecontrol treatment group. The specificity of the prognostic power of thetrained model includes a likelihood that the model will correctlyidentify of a subset of patients that benefit from experimentaltreatment. In some embodiments, comparing the first prognosticperformance and the second prognostic performance includes performingsubset survival analyses using respective predicted survival data fromthe experimental treatment group and the control treatment group.

In some embodiments, the extracted values for the features areprocessed, using the trained model, to predict respective survival datafor the first group of patients. The first group of patients belong toan experimental treatment group. Based on the predicted survival data, asubset of the first group of patients that responded to the experimentaltreatment is selected. In some embodiments, based on the predictedsurvival data, a subset of the features indicative of the subset of thefirst group of patients that responded to the experimental treatment isselected.

In some embodiments, values for features extracted from annotatedpathology images associated with a second group of patients areprocessed, using the trained model, to predict survival data for thepatients in the second group of patients. The second group of patientsbelongs to a treatment group in another clinical trial. A subset of thesecond group of patients that are expected to respond to treatment isselected.

In some embodiments, the features are selected from a group includingarea of epithelium, area of stroma, area of necrosis, area of cancercells, area of macrophages, area of lymphocytes, number of mitoticfigures, average nuclear grade, average distance between fibroblasts andlymphocytes, average distance between immunohistochemistry-positivemacrophages and cancer cells, standard deviation of nuclear grade,average distance between blood vessels and tumor cells.

In some embodiments, the trained model includes one or more of ageneralized linear model, a random forest, a support vector machine, agradient boosted tree, and another suitable model.

Still other aspects, embodiments, and advantages of these exemplaryaspects and embodiments, are discussed in detail below. Any embodimentdisclosed herein may be combined with any other embodiment in any mannerconsistent with at least one of the objects, aims, and needs disclosedherein, and references to “an embodiment,” “some embodiments,” “analternate embodiment,” “various embodiments,” “one embodiment” or thelike are not necessarily mutually exclusive and are intended to indicatethat a particular feature, structure, or characteristic described inconnection with the embodiment may be included in at least oneembodiment. The appearances of such terms herein are not necessarily allreferring to the same embodiment. The accompanying drawings are includedto provide illustration and a further understanding of the variousaspects and embodiments, and are incorporated in and constitute a partof this specification. The drawings, together with the remainder of thespecification, serve to explain principles and operations of thedescribed and claimed aspects and embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

Various aspects of at least one embodiment are discussed below withreference to the accompanying figures, which are not intended to bedrawn to scale. Where technical features in the figures, detaileddescription or any claim are followed by reference signs, the referencesigns have been included for the sole purpose of increasing theintelligibility of the figures, detailed description, and claims.Accordingly, neither the reference signs nor their absence is intendedto have any limiting effect on the scope of any claim elements. In thefigures, each identical or nearly identical component that isillustrated in various figures is represented by a like numeral. Forpurposes of clarity, not every component may be labeled in every figure.The figures are provided for the purposes of illustration andexplanation and are not intended as a definition of the limits of theinvention. In the figures:

FIG. 1 shows a tissue sample image in accordance with some embodimentsof the technology described herein;

FIG. 2 shows a tissue sample image with a polygon annotation inaccordance with some embodiments of the technology described herein;

FIG. 3 shows a tissue sample image with a point annotation in accordancewith some embodiments of the technology described herein;

FIG. 4 shows a tissue sample image with annotations in accordance withsome embodiments of the technology described herein;

FIG. 5 shows a heat map for a tissue sample image generated by astatistical model in accordance with some embodiments of the technologydescribed herein;

FIG. 6 shows an illustrative process for training a statistical model inaccordance with some embodiments of the technology described herein;

FIG. 7 schematically shows layers of a convolutional neural network inaccordance with some embodiments of the technology described herein;

FIGS. 8-9 show illustrative flowcharts for training a statistical modelto predict tissue characteristics for a pathology image in accordancewith some embodiments of the technology described herein;

FIG. 10 shows an illustrative flowchart for predicting tissuecharacteristics for a pathology image using a statistical model inaccordance with some embodiments of the technology described herein;

FIGS. 11-12 show illustrative subset survival analyses in accordancewith some embodiments of the technology described herein;

FIG. 13 shows an illustrative flowchart for training a model to predictsurvival time for a patient in accordance with some embodiments of thetechnology described herein; and

FIG. 14 shows a block diagram of a computer system on which variousembodiments of the technology described herein may be practiced.

DETAILED DESCRIPTION

Conventionally, tissue biopsies rely on human analysis of stained tissuesamples using a microscope and techniques primarily developed over ahundred years ago. Pathologists study and identify certain establishedcharacteristics in tissue samples that are indicative of disease, suchas cancer. Pathologists typically undergo years of specialized trainingin diagnostic analysis of tissue samples but, their interpretation ofsamples is still subject to human error. Furthermore, reliance onspecialized human analysis poses a significant rate limitation andincurs great expense in diagnosing disease from tissue samples.Additionally, current techniques still rely on identifying patterns andfeatures detectable by the human eye and require progression of thedisease to a level at which those features are identifiable.

FIG. 1 shows a tissue sample image 100 in accordance with someembodiments of the technology described herein. Tissue images annotatedin accordance with the techniques described herein may be microscopicimages of tissue samples extracted from a patient. The tissue images maybe obtained by using an imaging instrument to create images of slides onwhich tissue slices are mounted. The tissue slices mounted on the slidesmay have been taken from tissue samples, such as biopsy or autopsyspecimens. The tissue samples may have been processed prior to capturingof images. For example, the tissue samples may have been fixed, stained,labeled, washed, or dehydrated. The samples may be taken from any tissuethat indicates the presence or absence of a pathological condition. Forexample, the tissue image may include a portion of a tumor. The imagemay be of a tissue that provides evidence of the presence or absence ofa disease or condition, such as cancer, Alzheimer's disease, Parkinson'sdisease, diabetes, cystic fibrosis, sickle cell anemia, or an autoimmunedisease. For example and without limitation, the tissue may be from atumor or from the liver, lung, breast, ovary, uterus, cervix, vagina,testicle, spleen, lymph node, bladder, kidney, brain, esophagus,stomach, intestine, gall bladder, mouth, lip, nose, pancreas, prostate,colon, skin, or any other organ that may be suspected of having a tumor.

Tissue samples may include biopsied tissue obtained, for example,through core needle biopsy. The samples may be paraffin-embedded and maybe sectioned into slices prior to staining. Tissue samples may bestained using any stain selected to highlight cellular structures orother features of interest useful in tissue analysis. The tissue samplesmay, for example, be prepared by hematoxylin and eosin stain (H&Estain). Examples of general staining methods include, but are notlimited to, hematoxylin and eosin (H&E), trichrome, periodic acid Schiff(PAS), autoradiography, enzyme histochemistry, immuno-fluorescence, andimmunohistochemistry. Specific stains include, but are not limited to,acid fuchsin, Aldehyde Fuchsin, Alician Blue, Alizarin Red S, AlkalinePhosphatase, aniline blue, Azan Stain, biebrich scarlet, BielschowskyStain, Cajal Stain, chromotrope 2R, Congo Red, Cresyl Violet, Eosin,fast green FCF, Fontana-Masson, Giemsa Stain, Golgi Stain, GomoriTrichrome, Heidenhain's AZAN trichrome stain, Hematoxylin, IronHematoxylin, light green SF yellowish, Luna Stain, Luxol Fast Blue,Mallory Trichrome, martius yellow, Masson Trichrome, Melanin Stains,methyl blue, milling yellow, Movat's Pentachrome, Mucicarmine, MucinStains, Myloperoxidase (MPO), Nissl Stains, Nuclear Fast Red, Oil Red 0,orange G, Orcien Stain, Osmium Tetroxide, Papanicolaou Stain, Perl'sIron Stain, phloxine, Phosphotungstic Acid-Hematoxylin (PTAH), picricacid, PicroSirius Red (polarized), ponceau 6R, Prussian Blue, ReticularFiber Stain, Romanowsky Stains, Safranin 0, Schmorl's Stain, SilverStains, Sudan Stains, Tartrazine, tartrazine, Toluidine Blue, VanGieson, Verhoeff Stain, Von Kassa Stain, water blue, Weigert's ElasticStain, Wright's Stain, and xylidine ponceau.

The tissue samples may be immune-stained with anti-cytokeratin antibody.The tissue samples may be prepared by yet other methods. For example, atissue sample may be prepared by Papanicolaou stain (Pap stain). Asample could optionally be labeled by antibodies or probes, e.g., eitherof which could be fluorescently labeled or conjugated to elementalisotopes for mass spectrometry. Tissue staining may compriseimmunohistochemistry staining using, for example, labelled antibodiestargeting proteins of interest or primary followed by secondaryantibodies where the primary antibodies target proteins of interest andthe secondary antibodies target the primary antibodies and carry, forexample, a fluorescent or otherwise reporter detectable through knownimaging techniques. Tissue staining such as immunohistochemistry may beperformed on an automated platform such as those available from VentanaMedical Systems, Inc. (Tucson, Ariz.). Tissue sample images may becaptured using an imaging instrument such as a microscope and digitalcamera and corresponding software.

Any suitable imaging instrument may be used to obtain a tissue imagefrom a tissue sample on a slide. In some embodiments, a suitable imaginginstrument includes an Olympus BX41 microscope in combination with aDP21 2 MP camera and CellSens software all available from OlympusCorporation (Center Valley, Pa.). Another suitable imaging instrumentincludes the Aperio ScanScope CS-0, Aperio AT2, and Aperio eSlidemanager and web browser all available from Leica Biosystems, Inc.(Buffalo Grove, Ill.). Stained tissue images may be acquired using, forexample, a high resolution whole-slide scanner such as the NanozoomerWhole Slide Scanner from Hamamatsu (Hamamatsu City, Shizuoka Pref.,Japan). Once tissue sample images are acquired, either for training dataor from a test sample, the image data may be provided to a systemconfigured to process the image data using, for example, a statisticalmodel. FIG. 2 shows a tissue sample image 200 that has been annotatedwith a polygon annotation 204. The polygon annotation 204 may have beendrawn, for example, by a pathologist or other medical professional toindicate a particular tissue type within the annotated region. Forexample, the pathologist may have drawn the polygon annotation 204 usinga user interface of a computer system. The annotated tissue sample imagemay be used as training data for training a statistical model to predicttissue characteristics for a pathology image. For example, thestatistical model may be trained to predict whether or not tissue sampleimages of lymph nodes contain indicia of breast cancer. Tissue sampleimage 200 also includes a subset of pixels in the image designated astraining patch 202. Training patch 202 includes the polygon annotation204 of a tissue characteristic category, for example, the categorycancer epithelium. The size of the training patch may be selected to bea size suitable for training the statistical model. For example, thetraining patch 202 may be of size 222 pixels by 222 pixels or anothersize which is suitable for using as input training data to train astatistical model (e.g., a convolutional neural network). In someembodiments, a tissue sample image may include a large number of pixels(e.g., 50,000 pixels by 50,000 pixels), and multiple training patcheshaving smaller numbers of pixels (e.g., 222 pixels by 222 pixels) may bedefined within the tissue sample image as a set of training patches.

The training patches in the set may include annotations of tissuecharacteristics from, e.g., a pathologist. In some embodiments, lessthan 1% of the sample image is initially annotated. In some embodiments,less than 5% of the sample image is initially annotated. Each of theannotations is associated with a tissue characteristic category,examples of which include, but are not limited to, cancer epithelium,cancer stroma, background, normal tissue, necrosis, lymphoid,macrophage, lymphocyte, fibroblast, plasma cell, pulmonary macrophage,melanoma, pigmented macrophage, endothelial cell, mitotic figure,nucleoli, nuclear pleomorphism, nerve, adipocyte, peri-neural invasion,epithelial and epithelial tubule formation, or another suitable tissuecharacteristic category. According to one aspect, a statistical modelthat is trained on pathology images that are sparsely annotated bypathologists (e.g., drawn in an online application) may be capable ofpredicting additional annotations for other unlabeled portions of apathology image.

In some embodiments, training patches are sampled from one or morepathology images to maintain a uniform distribution of tissuecharacteristic categories in the set of training patches. For example,if the statistical model is to be trained on four different categoriesof annotations, an equal number of training patches from each of thefour categories may be sampled as training data. A statistical modeltrained on a set of training patches where tissue characteristiccategories are uniformly distributed may provide improved predictionperformance over another statistical model trained on a set of trainingpatches with a non-uniform distribution. In some embodiments, thetraining patches are sampled in a distribution that differs from thedistribution of annotations in the training image. In some embodiments,approximately one million training patches are included in the set. Insome embodiments, the statistical model is trained on multiple pathologyimages, e.g., at least 50 such images. The pathology images may belongto different patients having the same disease.

The statistical model may include one or more of a support vectormachine, a neural network, a convolutional neural network, a regression,a random forest, a clustering, a Bayesian network, reinforcementlearning, metric learning, a genetic algorithm, or another suitablestatistical model. In some embodiments, the statistical model is aconvolutional neural network having input dimensions of 217 pixels by217 pixels, whereas the training patch size is 222 pixels by 222 pixels.The additional five pixels in each dimension may be used for randomresampling for data augmentation. For example, the original patch of 222pixels by 222 pixels may be randomly resampled to generate multipletraining patches of 217 pixels by 217 pixels for input to thestatistical model. Augmenting the training data in this manner toprovide more training patches for the statistical model to train maylead to faster training time and/or improved predictive performance.

Throughout this disclosure, a convolutional neural network is used as anexample of a statistical model that may be used in accordance with someembodiments. However, it should be appreciated that other types ofstatistical models may alternatively be used, and embodiments are notlimited in this respect. Other types of statistical models that may beused include a support vector machine, a neural network, a regressionmodel, a random forest, a clustering model, a Bayesian network,reinforcement learning, metric learning, a genetic algorithm, or anothersuitable statistical model. More details for training the convolutionalneural network are provided with respect to FIG. 7.

FIG. 3 shows a tissue sample image 300 that has been annotated withpoint annotations, e.g., 304 and 306. Training patches that relate toannotated portions of this tissue sample image may be used as trainingdata for training a statistical model to predict tissue characteristicsfor a pathology image. The statistical model may be trained in a mannersimilar to that described with respect to FIG. 2. As shown, sample image300 includes training patch 302 which defines a subset of pixelsassociated with the point annotation 304. Training patch 302 may beselected to be a size suitable for training the statistical model. Forexample, the training patch 302 may be of size 102 pixels by 102 pixels,or any other size which is suitable for input to a convolutional neuralnetwork or other statistical model. More details for training thestatistical model (e.g., a convolutional neural network) are providedwith respect to FIG. 7.

In some embodiments, the training data includes training patches for a“background” tissue characteristic category. In order to obtain adistribution that is suitable for identifying point annotations,training patches for the background category may be added to thetraining data such that the training patches for this category arepositioned a particular distance (e.g., a certain radius in number ofpixels) from an annotated point in the image and represent backgroundtissue that is not associated with an annotation. In some embodiments,the training data includes at least some training patches that have anannotation located at or near the center pixel of the training patch.The annotation at or near the center of the training patch may includean annotation associated with a center pixel or group of pixelsincluding the center pixel of the training patch. Additionally oralternatively, the annotation at or near the center of the trainingpatch may include an annotation associated with one or more pixelswithin a certain distance from the center pixel of the training patch.Defining training patches in this way may result in the convolutionalneural network trained to output a high probability for the tissuecharacteristic category associated with the point annotation when thepoint annotation is located at or near the center of a portion of theimage being processed rather than outputting the high probability whenthe point annotation is present in the portion of the image beingprocessed, but is not located at or near the center pixel of the imageportion. In some embodiments, the network architecture trained topredict point annotations (e.g., those described with respect to FIG. 3)may have fewer layers or nodes than the network architecture trained topredict polygon annotations (e.g., those described with respect to FIG.2).

In some embodiments, the output of the network architecture trained topredict point annotations may be combined with the output of the networkarchitecture trained to predict polygon annotations to obtainpredictions for annotations that may be more accurate that using theoutput of a single network architecture. For example, a networkconfigured to process smaller patches has access to a smaller portion ofthe image and hence has less context for predicting a particular pointannotation for the patches being processed. Combining the output of thenetwork configured to processes smaller patches with an output of anetwork that considers larger portions of the image for annotation mayimprove the annotation prediction due to the context that the largeportion of the image provides.

FIG. 4 shows a tissue sample image 400 that has been annotated withtissue category characteristics in accordance with some embodiments ofthe technology described herein. Although annotations and imagesprovided as input to a statistical model may not (or may) have theliteral, human-readable format as illustrated, the annotations shown inFIG. 4 represent different types of informative annotations that may beprovided as input to a statistical model for training as describedabove. The statistical model may be configured to identify features andassociate the identified features with medical conditions. Thus where,for example, a portion of an image is annotated as, e.g., “hyperplasia,”the statistical model may be configured to respond to the presence anddistribution of an abundance of mitotic spindles in that portion of theimage and when this response is repeated over millions of patchesthroughout training the statistical model may be trained to identifyhyperplasia when the same pattern appears in a sample image from apatient that has not been annotated or has been sparsely annotated by apathologist.

FIG. 5 shows a heat map 500 for a tissue sample image generated by astatistical model in accordance with some embodiments of the technologydescribed herein. The heat map 500 includes annotations for some or alltissue characteristic categories identified in the tissue sample image.

FIG. 6 shows an illustrative process 600 for training a statisticalmodel to generate, among other things, the heat map 500, in accordancewith some embodiments of the technology described herein. At act 602, apathology image, such as the tissue image described with respect to FIG.1, is received. At act 604, a set of training patches, each of whichincludes subsets of pixels in the pathology image are defined andcorresponding annotations are associated with each of the trainingpatches in the set, as described, for example, with respect to FIGS. 2and 3. At act 606, the set of training patches and correspondingannotations are provided as input to a statistical model, such as aconvolutional neural network, to train the statistical model to predictthe corresponding annotations using a supervised learning technique. Insome embodiments, the statistical model is trained on the set oftraining patches and corresponding annotations along with other clinicalmetadata values, such as age, gender, clinical measurements, predicteddiagnosis by pathologist, etc. These additional values may be receivedwith the pathology image and may provide the statistical model with moreinformation on the patient. In the case where the statistical model is aconvolutional neural network, these additional values may be input atany of the layers, such as the fully-connected layers. At act 608, thetrained statistical model is used to associate annotations for part orall of a pathology image using the predicted annotations, with theresultant annotated image being represented as a heat map, an example ofwhich is shown in FIG. 5. At act 610, the annotated pathology image issupplied to an annotator, such as a pathologist, to validate thepredicted annotations. If one or more of the predicted annotations ismarked as inaccurate, the predicted annotations may be updated to adifferent tissue category as supplied by the annotator, and informationrelated to the updated annotation may be supplied as updated trainingdata for retraining the statistical model. If the predicted annotationsare marked as accurate, the predicted annotations may be associated withcorresponding portions of the pathology image, and the associations maybe stored on a storage device.

In some embodiments, the statistical model may include a convolutionalneural network. The convolutional neural network may be fullyconvolutional or may have one or more fully connected layers. In someembodiments, the statistical model may be a different type of neuralnetwork model such as, for example, a recurrent neural network, amulti-layer perceptron, and/or a restricted Boltzman machine. It shouldbe appreciated that the statistical model is not limited to beingimplemented as a neural network and, in some embodiments, may be adifferent type of statistical model that may be used to assign labels toone or more portions of a pathology image. For example, the statisticalmodel may be any suitable type of non-linear regression model such as arandom forest regression model, a support vector regression model, or anadaptive basis function regression model. As another example, thestatistical model may be a Bayesian regression model or any othersuitable Bayesian Hierarchical model. In some embodiments, a neuralnetwork includes an input layer, an output layer, and one or more hiddenlayers that define connections from the input layer to the output layer.Each layer may have one or more nodes. For example, the neural networkmay include at least 5 layers, at least 10 layers, at least 15 layers,at least 20 layers, at least 25 layers, at least 30 layers, at least 40layers, at least 50 layers, or at least 100 layers.

In some embodiments, the training data is provided to an input layer ofa neural network. The training data may include a large number oftraining patches. The neural network may use or include a section ofcode or a script (e.g., in Python or Ruby) that analyzes the trainingpatches of the images and, at each patch, provides pixel intensityvalues from that patch of the image to one of the nodes of the inputlayer. Each patch may be read into one node of the input layer until allor substantially all of image has been provided as input to the inputlayer. Having received the training data at the input layer, the neuralnetwork may represent the features associated with the disease at nodesof at least one hidden layer connected to the input layer. The networkmay interrogate slices of tumors to represent features characteristic ofa condition of interest such as cancer. In some embodiments, thetraining data may include training patches from patients that are cancerfree and the neural network may identify features that differentiatebetween cancer positive and cancer free tissues. FIG. 7 provides detailsfor training a convolutional neural network in accordance with someembodiments to predict annotations for pathology images using thetraining data.

In some embodiments, the results are shown to one or more annotators viaa user interface through which the annotator can adjust the results. Theannotator may draw new polygons or points to indicate areas in the imagefor annotation that are different than the portions of the imageassociated with the predicted annotation(s). For example, if thepredicted annotation associates certain pixels in the pathology image tocancer epithelium, and the annotator determines that the annotatedpixels should instead be annotated as the stroma category, the annotatormay draw a polygon annotation associated with the stroma category aroundthe appropriate region of pixels in the image. In some embodiments, anetwork of pathologists is deployed for tasks, such as quality control,whether to input an image to be processed by the statistical model,handle requests for specific types of annotations, or validate resultsof outputs provided by the trained statistical model. For example,validation may be performed to ensure that the output of the trainedstatistical model is at least as good as an “average” pathologist.

In some implementations, a pathologist in the network may provideannotations for regions (e.g., in the form of polygon annotations) orcells (e.g., in the form of point annotations) in a pathology image. Thetissue characteristic category of the annotations may be specified tothe pathologist, and input requested only for annotations of thespecified tissue characteristic category, to ensure that the data iscollected in a structured way instead of pathologists simply inputtingtext, e.g., tissue characteristic category, for each annotation theyprovide. For example, a user interface configured to display thepathology image may provide a drop down menu and/or a selection toolthat enables the pathologist to select from among a fixed set of tissuecharacteristic categories. The pathologist may interact with the userinterface to create annotations on images that do not display the outputof a trained statistical model (e.g., overlaid heat maps), or thepathologist may create the annotations on heat maps output by astatistical model in an attempt to correct errors made by thestatistical model when predicting annotations for a pathology image. Inanother example, the pathologist may perform quality control onpathology images before they are processed. Such quality control mayinclude, but is not limited to, determining whether the images areblurry, contain folds, or include other artifacts, such as marker stain.In yet another example, the pathologists may verify metadata associatedwith the image such as the organ of the tissue, the stain applied to theimage, or other suitable metadata.

In some embodiments, feedback on predicted annotations from thepathologist is used to implement a training technique described furtherbelow. A typical dataset of pathology images may include example imagesdepicting tissues that have cancer, and other tissues that arecharacterized as normal or healthy (e.g., do not have cancer). If amodel trained to identify cancer cells predicts an annotation for cancercells on a portion of an image that is characterized as normal tissue,it may be determined that the trained model has difficulty classifyingthis portion of the image and should be retrained to improve the abilityof the model to accurately classify such image portions. Examples ofimage portions where the model output provided incorrect classificationsand should be retrained on may be referred to as “hard negatives.” Suchexamples may be added back to the training set to make the model morerobust. This same technique may be applied to pathology images thatcontain cancer but are sparsely annotated. Instead of automaticallyincluding samples in the training data, since the slides are typicallynot exhaustively labeled, pathologist indications for inaccurateannotations may be used as hard negatives for retraining and improvingthe ability of the statistical model to make accurate annotationpredictions.

FIG. 7 shows a convolutional neural network 700 that may be used topredict annotations for a pathology image in accordance with someembodiments of the technology described herein. For example,convolutional neural network 700 may be used at act 606 (FIG. 6) topredict annotations for a pathology image. The convolutional neuralnetwork may be used because such networks are suitable for analyzingvisual images. The convolutional neural network may require nopre-processing of a visual image in order to analyze the visual image.The convolutional neural network may analyze the visual image based oninput taken in a patch by patch sequence from the visual image. Asshown, the convolutional neural network comprises an input layer 704configured to receive information about the image 702 (e.g., pixelvalues for all or one or more portions of a pathology image), an outputlayer 708 configured to provide the output (e.g., a classification), anda plurality of hidden layers 706 connected between the input layer 704and the output layer 708. The plurality of hidden layers 706 includeconvolution and pooling layers 710 and fully connected layers 712.

The input layer 704 may be followed by one or more convolution andpooling layers 710. A convolutional layer may comprise a set of filtersthat are spatially smaller (e.g., have a smaller width and/or height)than the input to the convolutional layer (e.g., the image 702). Each ofthe filters may be convolved with the input to the convolutional layerto produce an activation map (e.g., a 2-dimensional activation map)indicative of the responses of that filter at every spatial position.The convolutional layer may be followed by a pooling layer thatdown-samples the output of a convolutional layer to reduce itsdimensions. The pooling layer may use any of a variety of poolingtechniques such as max pooling and/or global average pooling. In someembodiments, the down-sampling may be performed by the convolution layeritself (e.g., without a pooling layer) using striding.

The convolution and pooling layers 710 may be followed by fullyconnected layers 712. The fully connected layers 712 may comprise one ormore layers each with one or more neurons that receives an input from aprevious layer (e.g., a convolutional or pooling layer) and provides anoutput to a subsequent layer (e.g., the output layer 708). The fullyconnected layers 712 may be described as “dense” because each of theneurons in a given layer may receive an input from each neuron in aprevious layer and provide an output to each neuron in a subsequentlayer. The fully connected layers 712 may be followed by an output layer708 that provides the output of the convolutional neural network. Theoutput may be, for example, an indication of which class, from a set ofclasses, the image 702 (or any portion of the image 702) belongs to. Theconvolutional neural network may be trained using a stochastic gradientdescent type algorithm or another suitable algorithm. The convolutionalneural network may continue to be trained until the accuracy on avalidation set (e.g., held out images from the training data) saturatesor using any other suitable criterion or criteria.

It should be appreciated that the convolutional neural network shown inFIG. 7 is only one example implementation and that other implementationsmay be employed. For example, one or more layers may be added to orremoved from the convolutional neural network shown in FIG. 7.Additional example layers that may be added to the convolutional neuralnetwork include: a pad layer, a concatenate layer, and an upscale layer.An upscale layer may be configured to upsample the input to the layer.An ReLU layer may be configured to apply a rectifier (sometimes referredto as a ramp function) as a transfer function to the input. A pad layermay be configured to change the size of the input to the layer bypadding one or more dimensions of the input. A concatenate layer may beconfigured to combine multiple inputs (e.g., combine inputs frommultiple layers) into a single output.

Convolutional neural networks may be employed to perform any of avariety of functions described herein. For example, a convolutionalneural network may be employed to predict tissue characteristics for apathology image. It should be appreciated that more than oneconvolutional neural network may be employed to make predictions in someembodiments. For example, a first convolutional neural network may betrained on a set of annotated pathology images and a second, differentconvolutional neural network may be trained on the same set of annotatedpathology images, but magnified by a particular factor, such as 5×, 10×,20×, or another suitable factor. The first and second neural networksmay comprise a different arrangement of layers and/or be trained usingdifferent training data.

An example implementation of a convolutional neural network isillustrated below in Table 1. The convolutional neural network shown inTable 1 may be employed to classify an input image (e.g., a pathologyimage). For example, the convolutional network shown in Table 1 may beconfigured to receive an input pathology image of size 217 pixels by 217pixels and provide an output that is indicative of one or more tissuecharacteristics or labels for the pathology image, e.g., four to eighttissue characteristics or labels. In Table 1, the sequence of the layersis denoted by the “Layer Number” column, the type of the layer isdenoted by the “Layer Type” column, and the input to the layer isdenoted by the “Input to Layer” column.

TABLE 1 Example Layer Configuration for Convolutional neural network #Layer Layer Filters/ Filter Activation Drop- Input to Number Type UnitsSize Stride Function out Layer 1 Input Input Layer Image 2 Convo- 96 7 3ReLU Output lution of Layer Layer 1 3 Pooling 3 2 Output Layer of Layer2 4 Convo- 256 5 1 ReLU Output lution of Layer Layer 3 5 Pooling 3 2Output Layer of Layer 4 6 Convo- 384 3 1 ReLU Output lution of LayerLayer 5 7 Convo- 384 3 1 ReLU Output lution of Layer Layer 6 8 Convo-256 3 1 ReLU Output lution of Layer Layer 7 9 Pooling 3 2 ReLU OutputLayer of Layer 8 10 Fully 2048 ReLU drop- Output Connected out of Layer(0.5) Layer 9 11 Fully 2048 ReLU drop- Output Connected out of Layer(0.5) Layer 10 12 Fully # labels soft- Output Connected max of LayerLayer 11

Another example implementation of a convolutional neural network isillustrated below in Table 2. The convolutional neural network shown inTable 2 may be configured to receive an input pathology image of size 97pixels by 97 pixels and provide an output that is indicative of one ormore tissue characteristics or labels for the pathology image, e.g.,four to eight tissue characteristics or labels. In Table 2, the sequenceof the layers is denoted by the “Layer Number” column, the type of thelayer is denoted by the “Layer Type” column, and the input to the layeris denoted by the “Input to Layer” column.

TABLE 2 Example Layer Configuration for Convolutional neural network #Layer Layer Filters/ Filter Activation Drop- Input to Number Type UnitsSize Stride Function out Layer 1 Input Input Layer Image 2 Convo- 96 7 3ReLU Output lution of Layer Layer 1 3 Pooling 3 2 Output Layer of Layer2 4 Convo- 256 5 1 ReLU Output lution of Layer Layer 3 5 Pooling 3 1Output Layer of Layer 4 6 Convo- 256 3 1 ReLU Output lution of LayerLayer 5 7 Convo- 256 3 1 ReLU Output lution of Layer Layer 6 8 Convo-256 3 1 ReLU Output lution of Layer Layer 7 9 Pooling 3 2 ReLU OutputLayer of Layer 8 10 Fully 1024 ReLU drop- Output Connected out of Layer(0.5) Layer 9 11 Fully 1024 ReLU drop- Output Connected out of Layer(0.5) Layer 10 12 Fully # labels soft- Output Connected max of LayerLayer 11

In some embodiments, the convolutional neural network does not includepadding between layers. The layers may be designed such that there is nooverflow as pooling or convolution operations are performed. Moreover,layers may be designed to be aligned. For example, if a layer has aninput of size N*N, and has a convolution filter of size K, with strideS, then (N−K)/S must be an integer in order to have perfect alignment.

In some embodiments, the output of the training process is a set ofneural networks. For example, the output of the training process areneural networks for different tasks, e.g., identifying cells oridentifying regions. In another example, the neural networks are trainedat different magnification factors. A network configured to processsmaller patches than another network has access to a smaller portion ofthe image and hence has less context for predicting a particular pointannotation for the patches being processed. Combining the output of thenetwork configured to process smaller patches with an output of anetwork that considers larger portions of the image for annotation mayimprove the annotation prediction due to the context that the largeportion of the image provides. For example, patches extracted from 20×magnification and/or from 5×, 10× and 20× magnification for a particularpathology image may be used to capture different types of features andcontext about where the cells/regions are located within the image. Insome embodiments, each of the networks at different magnificationfactors may be trained independently and the heat maps may be combinedusing a logical operation (e.g., a logical AND operation or a logical ORoperation). In some embodiments, another network may be trained on theoutputs of each of the networks at different magnification factors inorder to combine the outputs.

In some embodiments, the network is trained on patches along with one ormore features that describe the context of the corresponding patch. Forexample, the features may include the (x,y) coordinates of the patch,the distance of the patch to the nearest patch having a backgroundcategory, and other suitable contextual information. In someembodiments, output from a network trained to predict polygonannotations is provided as input to a network being trained to predictpoint annotations. The output from the network trained to predictpolygon annotations may be used to provide context to the pointannotation training data being used to train the network to predictpoint annotations.

FIGS. 8-9 show illustrative flowcharts for training a statistical modelto predict tissue characteristics for a pathology image in accordancewith some embodiments of the technology described herein.

Flowchart 800 illustrates an exemplary process for training astatistical model to predict one or more annotations for a pathologyimage. In flowchart 800, at act 802, annotated pathology images areaccessed. Each image includes at least one annotation describing atissue characteristic category for a portion of the image. For example,an image, such as the image 200, may include an annotation, such as theannotation 204, describing a tissue characteristic category, such as thecategory cancer epithelium. At act 804, a set of training patches and acorresponding set of annotations is defined using at least one annotatedpathology image. Each training patch in the set includes values obtainedfrom a respective subset of pixels in the annotated pathology image andis associated with a corresponding patch annotation determined based onan annotation associated with the subset of pixels. For example, atraining patch, such as the training patch 202, may be defined from theimage 200. The size of the training patch 202 may be selected to be asize suitable for training the statistical model. The training patch 202includes the corresponding annotation 204. At act 806, the statisticalmodel is trained based on the set of training patches and thecorresponding set of patch annotations. For example, the statisticalmodel, such as a convolutional neural network, may be trained asdescribed with respect to FIG. 6 and FIG. 7. The training data for thestatistical model may include the training patch 202 and thecorresponding annotation 204. At act 808, the trained statistical modelis stored on a storage device.

Flowchart 900 illustrates an exemplary process for receiving validationon predicted annotations of the trained statistical model from, e.g., apathologist, and retraining the statistical model if the predictedannotations are indicated to be inaccurate. In flowchart 900, at act902, an annotation of a tissue characteristic category is predicted foran unannotated portion of the image. The predicted annotation may beobtained from processing an unannotated portion of an annotatedpathology image using the trained statistical model. For example, asdescribed with respect to FIG. 6, the trained statistical model may beused to associate annotations for part or all of the pathology imageusing the predicted annotations, with the resultant annotated imagebeing represented as a heat map, an example of which is shown in FIG. 5.At act 904, the predicted annotation is presented via a user interfaceto a user. For example, the predicted annotation may be presented to apathologist within a user interface of a computer system for reviewingsuch annotations. At act 906, an indication of whether the predictedannotation is accurate is received via the user interface. For example,the pathologist reviewing the predicted annotation may enter aconfirmation that the predicted annotation is accurate using the userinterface of the computer system. In another example, the pathologistmay enter a different tissue category for the predicted annotationand/or draw a corrected polygon for the predicted annotation using theuser interface of the computer system. At act 908, it is determinedwhether the indication specifies that the predicted annotation isaccurate. If it is determined that the indication specifies that thepredicted annotation is accurate, at act 910, the unannotated portion ofthe image is annotated with the predicted annotation. For example, theunannotated portion of the image may be associated with the predictedannotation, and the association may be stored in a storage device. If itis determined that the indication specifies that the predictedannotation is not accurate, at act 912, the predicted annotation isupdated based on the received indication. For example, the category ofthe predicted annotation may be updated based on the indication. Theinformation related to the updated annotation may be supplied as updatedtraining data for retraining the statistical model. At act 914, a set oftraining patches is redefined from the annotated pathology images. Atact 916, the statistical model is retrained based on the redefined setof training patches and the respective annotations. At act 918, theretrained statistical model is stored on the storage device.

FIG. 10 shows a flowchart 1000 of an illustrative process for predictingtissue characteristics for a pathology image using a statistical modelin accordance with some embodiments of the technology described herein.The statistical model may be trained, for example, on annotatedpathology images, each of which includes at least one annotationdescribing tissue characteristics for one or more portions of the image.At act 1002, a pathology image to be analyzed is accessed. At act 1004,a trained statistical model is retrieved from a storage device. Thestatistical model may be trained on a set of training patches and acorresponding set of patch annotations derived from at least oneannotated pathology image. For example, the trained statistical modelmay be trained as described with respect to FIG. 8 and/or FIG. 9. Eachtraining patch in the set may include values obtained from a respectivesubset of pixels in the annotated pathology image and is associated witha corresponding patch annotation determined based on an annotationassociated with the respective subset of pixels. At act 1006, a set ofpatches is defined from the pathology image. Each patch in the set mayinclude a subset of pixels from the corresponding pathology image. Atact 1008, the set of patches is processed using the trained statisticalmodel to predict respective annotations for each patch in the set. Thepredicted annotations may be stored on the storage device.

In some aspects, after a convolutional neural network has been trained,the trained statistical model may be applied to partially or fullyannotate a pathology image, and features (e.g., distances betweenannotated lymphocyte pairs in the image) may be extracted from theannotated image. In some embodiments, a function is applied to theannotated pathology image to extract a feature of interest. For example,the feature of interest may be the average distance of lymphocytes tocancer cells in a cancer tumor region of the pathology image. Thetrained statistical model may be applied to fully annotate the pathologyimage with predicted lymphocyte annotations and predicted cancer cellannotations. In some embodiments, the trained statistical modelgenerates a single annotated pathology image (or heat map) with bothpredicted lymphocyte annotations and predicted cancer cell annotations.In some embodiments, the trained statistical model generates oneannotated pathology image for predicted lymphocyte annotations andanother annotated pathology image for predicted cancer cell annotations.Subsequently, a function may be applied to the fully annotated pathologyimage(s) to extract the feature. The function may locate the lymphocyteannotations present in the cancer tumor region, determine the distance(e.g., in microns, pixels, or another suitable metric) to the nearestcancer cell annotation (e.g., the cancer cell's nucleus) for eachlymphocyte annotation, and average all the determined distances.

In some embodiments, any number and types of features may be extractedfrom an annotated image. For example, multiple features may be extractedfrom annotated images of hematoxylin and eosin stain (H&E) andimmunohistochemistry (IHC) stained slides, and corresponding featurevalues may be used to calculate values for other features throughcombination of one or more of the extracted features. A non-limitingrepresentative list of such features includes area of epithelium, areaof stroma, area of necrosis, area of cancer cells, area of macrophages,area of lymphocytes, number of mitotic figures, average nuclear grade,average distance between fibroblasts and lymphocytes, average distancebetween immunohistochemistry-positive macrophages and cancer cells,standard deviation of nuclear grade, average distance between bloodvessels and tumor cells. Other suitable features may include featuresrelated to spatial distribution of cells, heterogeneity, and texture.

The extracted features may be used to predict entities of interest,e.g., survival time, drug response, patient level phenotype/molecularcharacteristics, mutational burden, tumor molecular characteristics(including genomic features (e.g., tumor mutational burden)),transcriptomic features (e.g., RNA signatures), protein expressionfeatures (e.g., CD8+T lymphocyte)), patient clinical outcomes (e.g.,prognosis, drug response, and diagnosis), and other suitable entities ofinterest. The entities may be input into a model, such as a generalizedlinear model, a random forest, a support vector machine, a gradientboosted tree, or another suitable model, for predicting entities ofinterest.

In some embodiments, one or more features are extracted from the heatmaps generated from the statistical model applied to pathology images.In one example, the pathology images may have been collected frompatients having participated in a clinical trial (e.g., a randomizedcontrolled trial for an experimental therapeutic). In a randomizedcontrolled trial, each patient is assigned to receive either theexperimental treatment (e.g., which may include a single drug orcombination of drugs) or the control treatment (e.g., a placebo).Clinical metadata associated with the patients in the clinical trialincluding, for example, treatment group, overall survival time,progression free survival time, and best objective response may bereceived. A model may be trained to predict patient survival outcomesfrom pathology image data (e.g., features extracted from annotatedpathology data) provided as input to the model during training andsurvival data (e.g., as output of the model) for patients who receivedthe experimental treatment. In some embodiments, the model is trained onfeatures extracted from annotated pathology data along with otherclinical metadata values, such as age, gender, clinical measurements,predicted diagnosis by pathologist, etc. These additional values mayprovide the model with more information on the patient and help improveprediction.

In some embodiments, a model may be trained to predict patient survivaloutcomes from pathology image data (e.g., features extracted fromannotated pathology data) and genomic data (e.g., tumor mutationalburden (TMB)) provided as input to the model during training andsurvival data provided as output of the model. In some embodiments, themodel may be trained on transcriptomic and/or protein expression datathat is used instead of or in addition to the genomic data.

In some embodiments, the genomic data, e.g., TMB, may be readilyavailable and received with the pathology image data. In someembodiments, the genomic data, e.g., TMB, may not be available and maybe predicted using a statistical model trained on pathology images andassociated genomic data. The statistical model may be trained in asimilar manner as described with respect to FIG. 8. The predictedgenomic data may be used to train the model for predicting patientsurvival outcomes in a similar manner as described above and withrespect to FIG. 13. In some embodiments, the statistical model may betrained to predict transcriptomic and/or protein expression data insteadof or in addition to the genomic data.

FIGS. 11-12 show illustrative subset survival analyses in accordancewith some embodiments of the technology described herein. In someembodiments, to determine the specificity of the model's prognosticpower for patients receiving the experimental treatment, the model,trained on survival data associated with images (or features extractedfrom images) for the patients that received experimental treatment, isused to predict survival data based on images (or features extractedfrom images) for patients that received the control treatment.

In some embodiments, the predicted survival data is sorted into a“Predicted Responder” group of patients expected to respond to thetreatment (experimental or control) and a “Predicted Non-Responder”group of patients expected to not respond to the treatment (experimentalor control). In order to determine the specificity of the model'sprognostic predictions, a hazard ratio and a 95% confidence interval maybe computed for the “Predicted Responder” and “Predicted Non-Responder”groups among patients receiving the experimental treatment. It may thenbe determined whether the confidence interval includes the hazard ratioof the “Predicted Responder” and “Predicted Non-Responder” groups amongthe patients that received the control treatment. If the confidenceinterval does not include the hazard ratio among the patients thatreceived the control treatment, it may be inferred that the prognosticpower of the predictive model is specific for the experimentaltreatment. The hazard ratio is defined as the ratio of the hazard ratescorresponding to the experimental treatment and the control treatment.For example, patients receiving the control treatment may not survive attwice the rate per unit time as the patients receiving the experimentaltreatment.

In some embodiments, the model's prognostic performance for patientsthat received the experimental treatment is compared to the model'sprognostic performance for patients who received the standard or controltreatment (1100, FIG. 11). In some embodiments, to determine theprognostic performance of a model, the survival difference between thetwo groups of patients, the “Predicted Responder” group and “PredictedNon-Responder” group, is assessed by computing a log-rank P-value and ahazard ratio for the hazard rates in the two groups of patients.

In some embodiments, to determine whether the model accuratelyidentifies a patient subset that is likely to benefit from theexperimental treatment compared to the standard or control treatment,subset survival analyses are performed to compare survival outcomes ofthe experimental treatment or control treatment among patients predictedby the model to respond to the experimental treatment. These results arecompared to those obtained among patients predicted by the model to notrespond to the experimental treatment (1200, FIG. 12). In someembodiments, the predicted survival data is sorted into a “ExperimentalTx” group of patients receiving experimental treatment (includingpredicted responders and predicted non-responders) and a “Standard Tx”group of patients receiving the standard or control treatment (includingpredicted responders and predicted non-responders). In order todetermine the ability of the model to identify a subset of patients thatbenefits from the experimental treatment, the hazard ratio and 95%confidence interval for the “Experimental Tx” and “Standard Tx” groupsamong the patients classified by the model to be predicted respondersmay be computed. It may then be determined whether the confidenceinterval includes the hazard ratio of the “Experimental Tx” and“Standard Tx” groups among the patients classified by the model as to bepredicted non-responders. If the confidence interval does not includethe hazard ratio among the predicted non-responders, it may be inferredthat the model identifies a subset of patients that benefits from theexperimental treatment.

In some embodiments, patient response to an experimental or controltreatment includes an objective response status (e.g., completeresponse, partial response, no response, progressive disease), overallsurvival time within a threshold (e.g., deceased within five years oralive at least 5 years), or another suitable indicator of patientresponse.

In some embodiments, machine learning methods are used to predictpatient survival from pathology image data and patient survival data. Astatistical model, trained using image data and pathologist “polygon” or“point” annotations, is used to label cells and tissue regions in apathology image using, for example, the techniques described above. Afeature vector of human-interpretable features is extracted from eachpathology image. A prognostic model is trained using any number ofmachine learning algorithms (e.g., regularized Cox regression,regularized logistic regression, random forest, support vector machines,etc.) based on the extracted feature values and the patient survivaltime. The performance of the trained model may be tested by applying themodel to extracted features from a pathology image for a new patient tomake a survival prediction on the new patient.

In a particular example, overall survival time is used for the survivaldata. A classifier, such as for example, an L1-regularized logisticregression, is trained to predict the binary outcome of (1) alive at 5years or (2) dead at 5 years. The Lambda parameter that controls modelsparsity is tuned using leave-one-out cross validation. This trainingand testing may be performed using cross-validation only and/or using anindependent set of samples for each of training and testing. Thetraining set may include about 200 samples, and the test set may includeabout 100 samples. Kaplan Meier curves may be used to compare thesurvival distributions of the predicted high-risk patients vs. thepredicted low-risk patients. The statistical significance of thesurvival curves may be assessed on the test cases (or held-out cases inthe case of cross-validation).

In some embodiments, the prognostic model described above may begeneralized in the setting where a prognostic model is trained for eachof a number of different treatments (e.g., 10 different prognosticmodels may be trained on the data from 10 different completed randomizedclinical trials). Then, for pathology images from a new sample, all 10models may be applied to the new sample, resulting in 10 differentsurvival predictions. The treatment with the longest predicted survivaltime (e.g., given an acceptable side effect profile/cost/etc.) may berecommended. Similarly, this approach may be used to recommend one ormore pharmacological agents and/or predict doses for treating anindividual patient.

FIG. 13 shows an illustrative flowchart 1300 for training a model topredict survival time for a patient in accordance with some embodimentsof the technology described herein. At act 1302, annotated pathologyimages associated with a group of patients in a clinical trial areaccessed. Each annotated pathology image may be associated with survivaldata for a respective patient. Each annotated pathology image mayinclude at least one annotation describing a tissue characteristiccategory for a portion of the image. For example, after a convolutionalneural network has been trained as described with respect to FIG. 6 andFIG. 7, the trained network may be applied to partially or fullyannotate a pathology image. In another example, the annotations for thepathology image may be received from a pathologist or other medicalprofessional. At act 1304, values for one or more features are extractedfrom each annotated pathology image. For example, the features may beextracted from annotated images of hematoxylin and eosin stain (H&E) andimmunohistochemistry (IHC) stained slides, and corresponding featurevalues may be used to calculate values for other features throughcombination of one or more of the extracted features. At act 1306, amodel is trained based on the survival data and the extracted values forthe features. Alternatively or additionally, the model may be trained topredict other predict entities of interest, such as drug response,patient level phenotype/molecular characteristics, mutational burden,tumor molecular characteristics (including genomic features (e.g., tumormutational burden)), transcriptomic features (e.g., RNA signatures),protein expression features (e.g., CD8+T lymphocyte)), patient clinicaloutcomes (e.g., prognosis, drug response, and diagnosis), and othersuitable entities of interest. At act 1308, the trained model is storedon a storage device.

FIG. 14 shows a block diagram of a computer system on which variousembodiments of the technology described herein may be practiced. Thesystem 1400 includes at least one computer 1433. Optionally, the system1400 may further include one or more of a server computer 1409 and animaging instrument 1455 (e.g., one of the instruments described above),which may be coupled to an instrument computer 1451. Each computer inthe system 1400 includes a processor 1437 coupled to a tangible,non-transitory memory device 1475 and at least one input/output device1435. Thus the system 1400 includes at least one processor 1437 coupledto a memory subsystem 1475 (e.g., a memory device or collection ofmemory devices). The components (e.g., computer, server, instrumentcomputer, and imaging instrument) may be in communication over a network1415 that may be wired or wireless and wherein the components may beremotely located or located in close proximity to each other. Usingthose components, the system 1400 is operable to receive or obtaintraining data such as tissue images and outcome data as well as testsample images generated by the imaging instrument or otherwise obtained.In certain embodiments, the system uses the memory to store the receiveddata as well as the model data which may be trained and otherwiseoperated by the processor.

In some embodiments, some or all of system 1400 is implemented in acloud-based architecture. The cloud-based architecture may offeron-demand access to a shared pool of configurable computing resources(e.g. processors, graphics processors, memory, disk storage, networkbandwidth, and other suitable resources). A processor in the cloud-basedarchitecture may be operable to receive or obtain training data such astissue images and outcome data as well as test sample images generatedby the imaging instrument or otherwise obtained. A memory in thecloud-based architecture may store the received data as well as themodel data which may be trained and otherwise operated by the processor.In some embodiments, the cloud-based architecture may provide a graphicsprocessor for training the model in a faster and more efficient mannercompared to a conventional processor.

Processor refers to any device or system of devices that performsprocessing operations. A processor will generally include a chip, suchas a single core or multi-core chip (e.g., 12 cores), to provide acentral processing unit (CPU). In certain embodiments, a processor maybe a graphics processing unit (GPU) such as an NVidia Tesla K80 graphicscard from NVIDIA Corporation (Santa Clara, Calif.). A processor may beprovided by a chip from Intel or AMD. A processor may be any suitableprocessor such as the microprocessor sold under the trademark XEONE5-2620 v3 by Intel (Santa Clara, Calif.) or the microprocessor soldunder the trademark OPTERON 6200 by AMD (Sunnyvale, Calif.). Computersystems may include multiple processors including CPUs and or GPUs thatmay perform different steps of the described methods. The memorysubsystem 1475 may contain one or any combination of memory devices. Amemory device is a mechanical device that stores data or instructions ina machine-readable format. Memory may include one or more sets ofinstructions (e.g., software) which, when executed by one or more of theprocessors of the disclosed computers can accomplish some or all of themethods or functions described herein. Each computer may include anon-transitory memory device such as a solid state drive, flash drive,disk drive, hard drive, subscriber identity module (SIM) card, securedigital card (SD card), micro SD card, or solid state drive (SSD),optical and magnetic media, others, or a combination thereof. Using thedescribed components, the system 1400 is operable to produce a reportand provide the report to a user via an input/output device. Aninput/output device is a mechanism or system for transferring data intoor out of a computer. Exemplary input/output devices include a videodisplay unit (e.g., a liquid crystal display (LCD) or a cathode ray tube(CRT)), a printer, an alphanumeric input device (e.g., a keyboard), acursor control device (e.g., a mouse), a disk drive unit, a speaker, atouchscreen, an accelerometer, a microphone, a cellular radio frequencyantenna, and a network interface device, which can be, for example, anetwork interface card (NIC), Wi-Fi card, or cellular modem.

It is to be appreciated that embodiments of the methods and apparatusesdiscussed herein are not limited in application to the details ofconstruction and the arrangement of components set forth in thefollowing description or illustrated in the accompanying drawings. Themethods and apparatuses are capable of implementation in otherembodiments and of being practiced or of being carried out in variousways. Examples of specific implementations are provided herein forillustrative purposes only and are not intended to be limiting. Inparticular, acts, elements and features discussed in connection with anyone or more embodiments are not intended to be excluded from a similarrole in any other embodiments.

Also, the phraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting. Any references toembodiments or elements or acts of the systems and methods hereinreferred to in the singular may also embrace embodiments including aplurality of these elements, and any references in plural to anyembodiment or element or act herein may also embrace embodimentsincluding only a single element. References in the singular or pluralform are not intended to limit the presently disclosed systems ormethods, their components, acts, or elements. The use herein of“including,” “comprising,” “having,” “containing,” “involving,” andvariations thereof is meant to encompass the items listed thereafter andequivalents thereof as well as additional items. References to “or” maybe construed as inclusive so that any terms described using “or” mayindicate any of a single, more than one, and all of the described terms.Any references to front and back, left and right, top and bottom, upperand lower, and vertical and horizontal are intended for convenience ofdescription, not to limit the present systems and methods or theircomponents to any one positional or spatial orientation.

Having thus described several aspects of at least one embodiment, it isto be appreciated that various alterations, modifications, andimprovements will readily occur to those skilled in the art. Suchalterations, modifications, and improvements are intended to be part ofthis disclosure, and are intended to be within the spirit and scope ofthe invention. Accordingly, the foregoing description and drawings areby way of example only.

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made throughout this disclosure and in any patentapplications incorporated by reference herein. All such documents arehereby incorporated herein by reference in their entirety for allpurposes.

What is claimed is:
 1. A method for training a statistical model topredict tissue characteristics for a pathology image, the methodcomprising: accessing a plurality of annotated pathology images, each ofwhich includes at least one annotation describing one of a plurality oftissue characteristic categories for a portion of the image; defining aset of training patches and a corresponding set of annotations using theat least one annotated pathology image, wherein each of the trainingpatches in the set includes values obtained from a respective subset ofpixels in the at least one annotated pathology image and is associatedwith a corresponding patch annotation determined based on an annotationassociated with the respective subset of pixels; training thestatistical model based on the set of training patches and thecorresponding set of patch annotations; and storing the trainedstatistical model on at least one storage device.
 2. The method of claim1, further comprising: processing, using the trained statistical model,at least one unannotated portion of an image of the plurality ofannotated pathology images to predict an annotation of one of theplurality of tissue characteristic categories for the unannotatedportion of the image; presenting, via a user interface, the predictedannotation to a user; receiving, via the user interface, an indicationof whether the predicted annotation is accurate; and annotating the atleast one unannotated portion of the image with the predicted annotationwhen the indication specifies that the predicted annotation is accurate.3. The method of claim 2, wherein when the indication specifies that thepredicted annotation is not accurate, the method further comprises:updating the predicted annotation based on the received indication;redefining a set of training patches from the plurality of annotatedpathology images; retraining the statistical model based on theredefined set of training patches and the respective annotations; andstoring the retrained statistical model on the at least one storagedevice.
 4. The method of claim 3, wherein the updated annotation has acategory determined based on the received indication.
 5. The method ofclaim 4, wherein the category for the updated annotation is a backgroundcategory.
 6. The method of claim 1, wherein defining the set of trainingpatches from the plurality of annotated pathology images comprises:including in the set of training patches, at least some training patchesfrom each of the plurality of tissue characteristic categories.
 7. Themethod of claim 6, wherein the set of training patches includes trainingpatches uniformly distributed across all of the plurality of tissuecharacteristic categories.
 8. The method of claim 6, wherein a firstdistribution across the plurality of tissue characteristic categories oftraining patches in the set of training patches differs from a seconddistribution across the plurality of tissue characteristic categories ofannotations in the plurality of annotations.
 9. The method of claim 1,wherein defining the set of training patches from the plurality ofannotated pathology images comprises: including in the set of trainingpatches at least one training patch associated an annotation for abackground category, wherein the at least one training patch is locateda radius of pixels from at least one of the plurality of annotations fora category other than the background category in the image.
 10. Themethod of claim 1, wherein defining the set of training patches from theplurality of annotated pathology images comprises: including in the setof training patches at least some training patches having an annotationat a center of the respective training patch.
 11. The method of claim 1,wherein at least one dimension of each of the training patches in theset is larger than a corresponding dimension of input to the statisticalmodel, wherein additional pixels in each of the training patches in theset are included when randomly resampling the respective training patchfor data augmentation.
 12. The method of claim 1, wherein thestatistical model comprises a convolutional neural network including aplurality of layers, wherein there is no padding applied to an output ofany layer of the plurality of layers.
 13. The method of claim 1, whereinthe statistical model comprises a convolutional neural network includinga plurality of layers, wherein at least one of the plurality of layers,having input of size N*N, a convolution filter of size K, and a strideS, is aligned such that (N−K)/S is an integer.
 14. The method of claim1, wherein the plurality of tissue characteristic categories includesone or more categories selected from a group consisting of cancerepithelium, cancer stroma, normal tissue, necrosis, lymphoid,macrophage, lymphocyte, fibroblast, plasma cell, pulmonary macrophage,melanoma, pigmented macrophage, endothelial cell, mitotic figure,nucleoli, nuclear pleomorphism, nerve, adipocyte, peri-neural invasion,epithelial and epithelial tubule formation.
 15. The method of claim 1,wherein the trained statistical model is a first trained statisticalmodel, wherein the method further comprises: magnifying the plurality ofannotated pathology images to create a magnified plurality of pathologyimages; defining a second set of training patches from the magnifiedplurality of annotated pathology images; training a second statisticalmodel based on the second set of training patches and respectiveannotations; and storing the trained second statistical model on atleast one storage device.
 16. The method of claim 15, furthercomprising: combining an output of the first trained statistical modeland an output of the second trained statistical model using a logicalAND operation or a logical OR operation.
 17. A system for training astatistical model to predict tissue characteristics for a pathologyimage, the system comprising: at least one computer hardware processor;and at least one non-transitory computer-readable storage medium storingprocessor-executable instructions that, when executed by the at leastone computer hardware processor, cause the at least one computerhardware processor to perform: accessing a plurality of annotatedpathology images, each of which includes at least one annotationdescribing one of a plurality of tissue characteristic categories for aportion of the image; defining a set of training patches and acorresponding set of annotations using the at least one annotatedpathology image, wherein each of the training patches in the setincludes values obtained from a respective subset of pixels in the atleast one annotated pathology image and is associated with acorresponding patch annotation determined based on an annotationassociated with the respective subset of pixels; training thestatistical model based on the set of training patches and thecorresponding set of patch annotations; and storing the trainedstatistical model on at least one storage device.
 18. The system ofclaim 17, wherein the processor-executable instructions further causethe at least one computer hardware processor to perform: processing,using the trained statistical model, at least one unannotated portion ofan image of the plurality of annotated pathology images to predict anannotation of one of the plurality of tissue characteristic categoriesfor the unannotated portion of the image; presenting, via a userinterface, the predicted annotation to a user; receiving, via the userinterface, an indication of whether the predicted annotation isaccurate; and annotating the at least one unannotated portion of theimage with the predicted annotation when the indication specifies thatthe predicted annotation is accurate.
 19. The system of claim 18,wherein when the indication specifies that the predicted annotation isnot accurate, the processor-executable instructions further cause the atleast one computer hardware processor to perform: updating the predictedannotation based on the received indication; redefining a set oftraining patches from the plurality of annotated pathology images;retraining the statistical model based on the redefined set of trainingpatches and the respective annotations; and storing the retrainedstatistical model on the at least one storage device.
 20. The system ofclaim 19, wherein the updated annotation has a category determined basedon the received indication.
 21. The system of claim 20, wherein thecategory for the updated annotation is a background category.
 22. Thesystem of claim 17, wherein defining the set of training patches fromthe plurality of annotated pathology images comprises: including in theset of training patches, at least some training patches from each of theplurality of tissue characteristic categories.
 23. The system of claim22, wherein the set of training patches includes training patchesuniformly distributed across all of the plurality of tissuecharacteristic categories.
 24. The system of claim 22, wherein a firstdistribution across the plurality of tissue characteristic categories oftraining patches in the set of training patches differs from a seconddistribution across the plurality of tissue characteristic categories ofannotations in the plurality of annotations.
 25. The system of claim 17,wherein defining the set of training patches from the plurality ofannotated pathology images comprises: including in the set of trainingpatches at least one training patch associated an annotation for abackground category, wherein the at least one training patch is locateda radius of pixels from at least one of the plurality of annotations fora category other than the background category in the image.
 26. Thesystem of claim 17, wherein defining the set of training patches fromthe plurality of annotated pathology images comprises: including in theset of training patches at least some training patches having anannotation at a center of the respective training patch.
 27. The systemof claim 17, wherein at least one dimension of each of the trainingpatches in the set is larger than a corresponding dimension of input tothe statistical model, wherein additional pixels in each of the trainingpatches in the set are included when randomly resampling the respectivetraining patch for data augmentation.
 28. The system of claim 17,wherein the statistical model comprises a convolutional neural networkincluding a plurality of layers, wherein there is no padding applied toan output of any layer of the plurality of layers.
 29. The system ofclaim 17, wherein the statistical model comprises a convolutional neuralnetwork including a plurality of layers, wherein at least one of theplurality of layers, having input of size N*N, a convolution filter ofsize K, and a stride S, is aligned such that (N−K)/S is an integer. 30.The system of claim 17, wherein the plurality of tissue characteristiccategories includes one or more categories selected from a groupconsisting of cancer epithelium, cancer stroma, normal tissue, necrosis,lymphoid, macrophage, lymphocyte, fibroblast, plasma cell, pulmonarymacrophage, melanoma, pigmented macrophage, endothelial cell, mitoticfigure, nucleoli, nuclear pleomorphism, nerve, adipocyte, peri-neuralinvasion, epithelial and epithelial tubule formation.
 31. The system ofclaim 17, wherein the trained statistical model is a first trainedstatistical model, wherein the processor-executable instructions furthercause the at least one computer hardware processor to perform:magnifying the plurality of annotated pathology images to create amagnified plurality of pathology images; defining a second set oftraining patches from the magnified plurality of annotated pathologyimages; training a second statistical model based on the second set oftraining patches and respective annotations; and storing the trainedsecond statistical model on at least one storage device.
 32. The methodof claim 31, the processor-executable instructions further cause the atleast one computer hardware processor to perform: combining an output ofthe first trained statistical model and an output of the second trainedstatistical model using a logical AND operation or a logical ORoperation.